Summary Loss of proteostasis is considered one of the process that contributes to aging. Among the different components of the proteostasis network, this program project (PP) focuses on Autophagy. During previous periods we have identified new types of selective autophagy, their interplay among them and with other components of the proteostasis network, new functions of autophagy beyond proteostasis maintenance, mechanisms responsible for autophagic pathways? malfunctioning in aging and the impact of this malfunctioning in organ proteostasis and function. The knowledge, technology and experimental tools developed by this PP allow now this project to answer two to fundamental questions in the context of Geroscience: 1) is there a bi-directional interplay between autophagy in peripheral organs and central nervous system and does this interconnection explains the non-phsicological comorbilities that associate with Alzhiemer?s disease and Related Dementias (AD/ADRD)? and 2) can prevention of aging of the autophagic system attenuate proteotoxicity associated with AD/ADRD, one of the most prevalent diseases of aging?. With this purpose and in close collaboration with the other components of this PP we will: 1) determine if models of AD-related brain proteotoxicity have disturbances in peripheral proteostasis and if that is true in peripheral patient cells; 2) analyze the effect of aging of the autophagy system in peripheral organs on the aged brain and in onset of AD-related proteotoxicity 3) investigate the effect of chemical or genetic enhancement of central and/or peripheral autophagy on brain aging and AD-proteotoxicity. Integration in the PP: this project will utilize experimental mouse models with AD-relate proteins to recapitulate the proteotoxicity of the AD brain, and the aging mouse groups generated by the Animal Core and shared by all the projects. Image-based analysis of the changes in peripheral and central autophagy will be done with the state-of-the-art image technology provided by the Image Core and treatment of the animal models with autophagy enhancers will be done with the Therapeutics Core. Mechanisms of intercommunication between peripheral and central autophagy will be investigated with P2, and the cross-talk between autophagic pathways with P4. Information on peripheral and central autophagy generated in these collaborative and on autophagic pathways in in the immune and hematopoietic system generated by P3 in the same models will be integrated at the Biostatistics Unit. Relevance to public health: Studies in this project may provide novel information on the bases of other comorbidities that affect AD/ADRD patients and on how they may contribute also to disease progression. If successful, the interventions proposed in this work may offer a proof-of-concept and prototype molecules for future development of drugs for treatment of neurodegenerative conditions that originate from proteotoxic insults by preventing aging of the autophagy system.